College 1e jaars Fase IV geneesmiddelenonderzoek

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1e jaars inleiding fase IV geneesmiddelen onderzoek blok FA107 Farmaceutische Wetenschappen

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  • College 1e jaars Fase IV geneesmiddelenonderzoek

    1. 1. Geneesmiddelenonderzoek Fase IV Rob Heerdink 10 juni 2009
    2. 2. Dr Rob Heerdink Pharmacoepidemiology & Pharmacotherapy Utrecht Institute for Pharmaceutical Sciences Universiteit Utrecht The Netherlands www.pharm.uu.nl/epithera
    3. 4. Ontwikkeling van geneesmiddelen discovery Discovery & screening Proof of Concept first administration to man registration & launch approx. 10-12 years 10,000 Pre-clinical development 15-30 Fase I/IIa 10-15 Fase IIb/III 1 5 preklinisch klinisch (I-III) fase 4
    4. 5. Een geneesmiddel komt op de markt
    5. 6. Science 2005; 307: 196-8.
    6. 9. Verschil tussen RCTs en de praktijk – aantal gebruikers Klinisch onderzoek De markt
    7. 12. “ It was easy money during the first trial, but that spinal tap really hurt.”
    8. 13. Echte patienten <ul><li>Leeftijd </li></ul>
    9. 14. Echte patienten <ul><li>Leeftijd </li></ul><ul><li>Kinetiek </li></ul>
    10. 15. Echte patienten <ul><li>Leeftijd </li></ul><ul><li>Kinetiek </li></ul><ul><li>Therapietrouw </li></ul>
    11. 16. Echte patienten <ul><li>Leeftijd </li></ul><ul><li>Kinetiek </li></ul><ul><li>Therapietrouw </li></ul><ul><li>Meerdere aandoeningen </li></ul><ul><li>Nemesis: </li></ul>geen 1 >1
    12. 17. Echte patienten <ul><li>Leeftijd </li></ul><ul><li>Kinetiek </li></ul><ul><li>Therapietrouw </li></ul><ul><li>Meerdere aandoeningen </li></ul><ul><li>Meerdere middelen </li></ul>
    13. 18. Are Subjects in Pharmacological Treatment Trials of Depression Representative of Patients in Routine Clinical Practice? Mark Zimmerman, M.D., Jill I. Mattia, Ph.D., and Michael A. Posternak, M.D Am J Psychiatry 159:469-473, March 2002 ‘ Van 346 patienten met ‘major depression’ voldoet slechts 14% aan de inclusiecriteria die algemeen gelden voor een trial met antidepressiva.’
    14. 19. RCTs <ul><li>In het overgrote deel van de trials naar nieuwere antipsychotica is haloperidol in een te hoge dosis gebruikt. </li></ul><ul><li>Hugenholtz et al, J Clin Psych (in press) </li></ul>
    15. 20. RCTs <ul><li>Hebben bijzondere deelnemers </li></ul><ul><li>Worden niet altijd goed uitgevoerd </li></ul><ul><li>Onderzoeken niet altijd de relevante vragen </li></ul><ul><li>There is a lack of well-designed trials into the effect of drugs in the management of aggression in psychiatric patients </li></ul><ul><li>Goedhard et al, J Clin Psych (in press) </li></ul>
    16. 21. comparator Heres et al. Am J Psych, Feb 2006 sponsored drug risperidon clozapine ziprasidone ami sulpiride Olanzapine (Lilly) 5 / 0 2 / 1 2 / 0 1 / 0
    17. 22. comparator Heres et al. Am J Psych, Feb 2006 sponsored drug olanzapine risperidon clozapine ziprasidone ami sulpiride Olanzapine (Lilly) 5 / 0 2 / 1 2 / 0 1 / 0 Risperidon (Janssen) 3 / 1 1 / 0
    18. 23. comparator Heres et al. Am J Psych, Feb 2006 sponsored drug olanzapine risperidon clozapine ziprasidone ami sulpiride Olanzapine (Lilly) 5 / 0 2 / 1 2 / 0 1 / 0 Risperidon (Janssen) 3 / 1 1 / 0 Clozapine (Novartis) 1 / 0 1 / 0
    19. 24. comparator Heres et al. Am J Psych, Feb 2006 sponsor drug olanzapine risperidon clozapine ziprasidone ami sulpiride Olanzapine (Lilly) 5 / 0 2 / 1 2 / 0 1 / 0 Risperidon (Janssen) 3 / 1 1 / 0 Clozapine (Novartis) 1 / 0 1 / 0 Ziprasidone (Pfizer) 1 / 1 Amisulpiride (Sanofi) 1 / 0
    20. 25. evidence based medicine ?
    21. 26. farmaco-epidemiologie medicine based evidence
    22. 27. NRC Handelsblad 6 juni 2009
    23. 28. Relevante praktijkvragen na registratie <ul><li>effect op harde eindpunten </li></ul><ul><li>lange termijn (neven)effecten </li></ul><ul><li>(meer)waarde tov andere geneesmiddelen </li></ul><ul><li>effect in niet onderzochte populaties </li></ul><ul><ul><li>kinderen </li></ul></ul><ul><ul><li>ouderen </li></ul></ul><ul><ul><li>zwangeren </li></ul></ul><ul><ul><li>multiple pathologie / geneesmiddelgebruik </li></ul></ul><ul><li>wie heeft wel baat, wie niet </li></ul><ul><li>minder frequent optredende bijwerkingen </li></ul>
    24. 29. Evaluatie van therapie: gouden standaard Randomised Controlled Clinical Trial (RCT) Randomiseren: waarom? Controlegroep: waarom? Blindering: waarom? Doel: Enige verschil tussen behandelde en niet-behandelde groep is de behandeling
    25. 30. Een experiment is heel vaak niet mogelijk Ethisch (bv. roken, aangeboren afwijkingen) Praktisch (bv. zeldzame bijwerking) Niet-experimenteel (observationeel) onderzoek Voorbeeld: Bijten dieren vaker tijdens volle maan?
    26. 31. Do animals bite more during a full moon? Bhattacharjee C et al. BMJ 2000;321:1559-61
    27. 32. DOMEIN Determinant(en) Eindpunt(en) tijd <ul><ul><li>wel / geen vergelijking </li></ul></ul><ul><ul><li>experiment of observationeel </li></ul></ul><ul><ul><li>retrospectief of prospectief </li></ul></ul>Onderzoeksopzet
    28. 33. Onderzoeks opzetten Case report Cross-sectioneel Case-control Follow-up (cohort) Trial
    29. 34. <ul><li>Case Report (‘Casus’) / Case serie </li></ul><ul><li>beschrijft een karakteristieke relatie bij één / enkele </li></ul><ul><li>patient(en) tussen determinant en uitkomst </li></ul><ul><li>voorbeelden: </li></ul><ul><li>ernstige leverschade na gebruik XTC </li></ul><ul><li>aangeboren afwijkingen door Thalidomide (Softenon) </li></ul><ul><li>etcetera, etcetera, etcetera </li></ul>
    30. 35. The Lancet, 1961
    31. 36. LETTER TO THE EDITOR THALIDOMIDE AND CONGENITAL ABNORMALITIES Sir, Congenital disorders are present in approximately 1.5% of babies. In recent months I have observed that the incidence of multiple severe abnormalities in babies delivered of women who were given the drug thalidomide ('Distaval') during pregnancy,as an anti-emetic or as a sedative, to be almost 20%. Have any of your readers seen similar abnormalities in babies delivered of women who have taken this drug during pregnancy? McBride WG. The Lancet, December 16, 1961: page 1358
    32. 37. Example cross-sectional study Polymorphisms of the LEP- and LEPR gene and obesity in patients using antipsychotic medication Gregoor et al J Clin Psychopharmacol (in press) Research question: are LEPR polymorphisms associated with increased BMI in antipsychotic users Study design: cross-sectional
    33. 38. Example : LEPR study Population: 200 patients using antipsychotics Determinants: LEPR Q223R and LEP promoter 2548G/A SNP polymorphisms Outcome: BMI
    34. 39. Example : LEPR study ** p<0.05 N BMI>30 Males QQ 30 6 (20%) QR 73 16 (21%) RR 31 8 (26%) Females QQ 17 12 (71%) ** QR 39 15 (39%) QR 10 4 (40%)
    35. 40. Indexed prevalence and incidence per year of antidepressant use during 1992-2001 (1992=1). Meijer et al. Eur J Clin Pharmacol (2004) 60: 57–61
    36. 41. Observational Cohort <ul><li>Group of individuals with common inclusion criteria is followed over time until an endpoint occurs. </li></ul>
    37. 43. Cohort study / Follow-up study Study population Exposed Non-exposed Disease + Disease + Disease - Disease -
    38. 44. A cohort study <ul><li>RR (myocardial infarction)* </li></ul><ul><li>Untreated normotensive and hypertensive men 1.0 (reference) </li></ul><ul><li>Treated hypertensive men DBP  90 mmHg 3.8 (1.3-11.0) </li></ul><ul><li>Treated hypertensive men DBP>90 mmHg 1.1 (0.5-2.6) </li></ul><ul><li>* adjusted for previous MI, CVA, IHD, IC, diabetes, SBP, duration of antihypertensive therapy, hypercholesterolemia, hypertriglyceridaemia, creatinin, obesity, use of cardiac glycosides, smoking. </li></ul><ul><li>Conclusion: In men treated for hypertension, DBP should not be reduced to lower than 90 mmHg </li></ul>Merlo J, et al. BMJ 1996;313:457-61.
    39. 45. Another cohort study <ul><li>RR (stroke) </li></ul><ul><li>Untreated “Candidates”* for treatment 1.0 (reference) </li></ul><ul><li>Treated Crude RR 0.49 (0.32-0.76) </li></ul><ul><li>Adjusted RR* 0.61 (0.39-0.97) </li></ul><ul><li>** Adjusted for age, sex, diabetes, total cholesterol, BMI, smoking, history of CVD </li></ul><ul><li>* Candidates for treatment defined according to Dutch guidelines on treatment of hypertension taking into account multifactorial risk of cardiovascular disease </li></ul>Klungel et al. Epidemiology 2001;12:339-34 4.
    40. 46. Follow up study versus RCT <ul><li>Similarities </li></ul><ul><ul><li>Use of same measures of frequency and association (RR, RD, AR, RRR, NNT, NNH) </li></ul></ul><ul><ul><li>Use of same analytical techniques (“survival” analysis: Kaplan Meier curves and Cox proportional hazard) </li></ul></ul><ul><li>Differences </li></ul><ul><ul><li>Follow-up vs. RCT: no randomisation and no blinding </li></ul></ul><ul><ul><ul><li>(outcome measurement sometimes blinded) </li></ul></ul></ul>Follow-up studies more vulnerable to bias
    41. 47. Cohort study / Follow-up study Study population Exposed Non-exposed Disease + Disease + Disease - Disease -
    42. 48. Case-control study Study Population Cases Controls Exposed Non-exposed Exposed Non-exposed
    43. 49. Voorbeeld case-control onderzoek <ul><li>Wat is het risico op borstkanker bij gebruik van SSRI antidepressiva? </li></ul><ul><li>Cases: vrouwen met borstkanker </li></ul><ul><li>Controles: vrouwen zonder borstkanker </li></ul><ul><li>Blootstelling:SSRIs </li></ul>
    44. 50. Coogan et al. Am J Epidemiol 2005
    45. 51. Meijer et al. Arch Int Med 2004
    46. 52. <ul><li>Beperkingen </li></ul><ul><li>Confounding? </li></ul><ul><li>Selectie bias? </li></ul><ul><li>Recall bias? </li></ul><ul><li>Conclusie? </li></ul><ul><li>Implicaties? </li></ul>
    47. 53. Grootste gevaar: confounding <ul><li>geassocieerd met de determinant </li></ul><ul><li>geassocieerd met het eindpunt </li></ul><ul><li>niet een intermediaire factor </li></ul>determinant eindpunt (bv. alcohol) (bv. MI) confounder (bv. leeftijd)
    48. 55. Lanes et al. Pharmacoepidemiol & Drug Saf 2000;9:113-7 Selective prescribing of meloxicam meloxicam ibuprofen n=5000 n=5000 recent use NSAIDs 49.8% 7.9% recent use H2 blockers 12.4% 4.0% recent use proton-pump inh. 11.1% 4.0% history of dyspepsia 38.4% 20.3% history of peptic ulcer 6.1% 3.1%
    49. 56. population to be prescribed a NSAID prescribed ibuprofen prescribed meloxicam prescriber’s decision younger healthier no GI history older GI history
    50. 58. Risk assessment
    51. 60. Registration of a drug is only the beginning of safety research

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